The present invention relates to a novel process for the preparation of ribonucleotide reductase inhibitors. The target compounds of the novel process described in this application are disclosed by McCarthy et al. in European Patent Application Publication No. 0 372 268 published Jun. 13, 1990. The previous synthesis of these compounds involved a seven step reaction sequence in which a uridine derivative was the required starting material. The uridine derivative was converted to the known ketone intermediate of structure (A) ##STR1## wherein V is oxy or methylene and Y is hydrogen, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy, following generally the procedure of Matsuda et al. [Chem. Pharm. Bull. 1988, 36(3), 945] in an eight step process from commercially available starting material that was labor intensive and involved multiple chromatographies. This intermediate was then subjected to olefination at the 2'-carbonyl to produce the exocyclic fluorovinyl sulfone followed by stannylation to provide the exocyclic (fluorovinyl) stannane. In the final step this compound was destannylated and the 3', 5'-hydrolysis were deprotected to provide the desired ribonucleotide reductase inhibitor in low yield.
The novel process of the present invention utilizes a cytidine derivative as the required starting material and provides the ribonucleotide reductase inhibitor in a more efficient five step reaction sequence. The process is more efficient than the process of McCarthy et al. in that it requires fewer chromatographies and results in an overall yield of greater than 25% for the five steps.
The present invention further provides the ribonucleotide reductase inhibitor in a four step reaction sequence and results in an overall yield of greater than 35%. In addition the present invention provides a method for stereoselectively preparing the (E)-isomer of the ribonucleotide reductase inhibitor.